Is COG6 p.Thr511= (c.1533A>T) pathogenic?

COG6 p.Thr511= (c.1533A>T) is classified Likely benign in COG6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-21). Ultra-rare (popmax 0.0166%, nfe); Associated with hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome.

How common is COG6 p.Thr511= (c.1533A>T) in the general population?

COG6 p.Thr511= (c.1533A>T) is ultra-rare (popmax 0.0166%, nfe) (gnomAD).

COG6 p.Thr511=

Q: What condition is associated with COG6 p.Thr511= (c.1533A>T)?

COG6 p.Thr511= (c.1533A>T) is associated with hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, COG6-congenital disorder of glycosylation (ClinVar).

Q: How is Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1533A>T · rs201542120 · VCV706019

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, nfe)

Conditions

hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.8	GERP -3.5
Overall
CADD	2.767	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% European (non-Finnish) · 196/1,179,112 alleles

Filtering AF 0.0147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.014%

Overall 0.0126% 203/1,612,778 alleles · ultra-rare exomes 186/1,460,574 · genomes 17/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0166%	6,016
Remaining individualsnot grpmax-eligible	0.0064%	15,616
Admixed American	0.00334%	29,943
African / African-American	0.00133%	74,970

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: COG6
Protein: p.Thr511=
Coding: c.1533A>T
MANE Select: NM_020751
dbSNP: rs201542120
Type: single nucleotide variant
Location: chr13:39719776 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.62

Full COG6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: COG6-congenital disorder of glycosylation

For Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

COG6 c.1167-24A>G Pathogenic/Likely pathogenic ★★ same condition
COG6 p.Arg171Ter Pathogenic ★★ same condition
COG6 p.Arg360Ter Pathogenic/Likely pathogenic ★★ same condition
COG6 p.Leu512Ter Pathogenic/Likely pathogenic ★★ same condition
COG6 c.*1532T>G Uncertain significance ★★ same condition
COG6 c.*52G>A Uncertain significance ★★ same condition
COG6 p.Ala13Thr Uncertain significance ★★ ⚠ same condition
COG6 p.Arg121His Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cog6-p-thr511 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown